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Specific Correlation Between the Major Chromosome 10Q26 Haplotype Conferring Risk for Age-Related Macular Degeneration and the Expression of HTRA1

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Molecular Vision 2017; 23:318-333 <http://www.molvis.org/molvis/v23/318> © 2017 Molecular Vision Received 5 December 2016 | Accepted 12 June 2017 | Published 14 June 2017 Specific correlation between the major chromosome 10q26 haplotype conferring risk for age-related macular degeneration and the expression of HTRA1 Sha-Mei Liao,1 Wei Zheng,1 Jiang Zhu,2 Casey A. Lewis,1 Omar Delgado,1 Maura A. Crowley,1 Natasha M. Buchanan,1 Bruce D. Jaffee,1 Thaddeus P. Dryja1 1Department of Ophthalmology; NIBR Informatics, Novartis Institutes for Biomedical Research, Cambridge, MA; 2Scientific Data Analysis, NIBR Informatics, Novartis Institutes for Biomedical Research, Cambridge, MA Purpose: A region within chromosome 10q26 has a set of single nucleotide polymorphisms (SNPs) that define a haplo- type that confers high risk for age-related macular degeneration (AMD). We used a bioinformatics approach to search for genes in this region that may be responsible for risk for AMD by assessing levels of gene expression in individuals carrying different haplotypes and by searching for open chromatin regions in the retinal pigment epithelium (RPE) that might include one or more of the SNPs. Methods: We surveyed the PubMed and the 1000 Genomes databases to find all common (minor allele frequency > 0.01) SNPs in 10q26 strongly associated with AMD. We used the HaploReg and LDlink databases to find sets of SNPs with alleles in linkage disequilibrium and used the Genotype-Tissue Expression (GTEx) database to search for correlations between genotypes at individual SNPs and the relative level of expression of the genes. We also accessed Encyclopedia of DNA Elements (ENCODE) to find segments of open chromatin in the region with the AMD-associated SNPs. Predicted transcription factor binding motifs were identified using HOMER, PROMO, and RegulomeDB software programs. Results: There are 34 polymorphisms within a 30-kb region that are in strong linkage disequilibrium (r2>0.8) with the reference SNP rs10490924 previously associated with risk for AMD. The expression of three genes in this region, PLEKHA1, ARMS2, and HTRA1 varies between people who have the low-AMD-risk haplotype compared with those with the high-AMD-risk haplotype. For PLEKHA1, 44 tissues have an expression pattern with the high-AMD-risk haplotype associated with low expression (rs10490924 effect size -0.43, p = 3.8 x 10-5 in ovary). With regard to ARMS2, the varia- tion is most pronounced in testes: homozygotes with the high-AMD-risk haplotype express ARMS2 at lower levels than homozygotes with the low-AMD-risk haplotype; expression in heterozygotes falls in between (rs10490924 effect size -0.79, p = 7.5 x 10-24). For HTRA1, the expression pattern is the opposite; the high-AMD-risk haplotype has higher levels of expression in 27 tissues (rs10490924 effect size 0.40, p = 1.5 × 10−7 in testes). None of the other 22 genes within one megabase of rs10490924, or any gene in the entire genome, have mRNA expression levels that correlate with the high- AMD-risk haplotype. More than 100 other SNPs in the 10q26 region affect the expression of PLEKHA1 and ARMS2 but not that of HTRA1; none of these SNPs affects the risk for AMD according to published genome-wide association studies (GWASs). Two of the AMD-risk SNPs (rs36212732 and rs36212733) affect transcription factor binding sites in proximity to a DNase I hypersensitive region (i.e., a region of open chromatin) in RPE cells. Conclusions: SNPs in chromosome 10q26 that influence the expression of onlyPLEKHA1 or ARMS2 are not associated with risk for AMD, while most SNPs that influence the expression ofHTRA1 are associated with risk for AMD. Two of the AMD-risk SNPs affect transcription factor binding sites that may control expression of one of the linked genes in the RPE. These findings suggest that the variation in the risk for AMD associated with chromosome 10q26 is likely due to variation in HTRA1 expression. Modulating HTRA1 activity might be a potential therapy for AMD. Age-related macular degeneration (AMD) is the leading some AMD-risk SNPs change the coding region of genes, cause of severe vision loss in older individuals. Single nucleo- most reside outside coding regions, suggesting potential tide polymorphisms (SNPs) in at least 34 loci influence the effects in regulating the expression of linked genes [2,3]. A risk for AMD [1], and the mechanisms by which these vari- set of closely linked SNPs on chromosome 10q26 is of special ants influence AMD are still being elucidated. Although interest since this chromosome has more influence on the risk for AMD than any other AMD region [1,4-7]; however, which gene in the region confers the risk remains unclear Correspondence to: Sha-Mei Liao, Department of Ophthalmology, [5,8-10]. Three genes are within 100 kilobase pairs (kb) of the Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA; Phone: (617) 871 4004; FAX: (617) SNPs associated with AMD. From the centromeric to telo- 871 5784; email: [email protected] meric ends of this region, the genes are pleckstrin homology Dr. Zheng now at GNS Healthcare, Cambridge, MA domain-containing family A member 1 (PLEKHA1; gene ID: 318 Molecular Vision 2017; 23:318-333 <http://www.molvis.org/molvis/v23/318> © 2017 Molecular Vision TABLE 1. THE 34 POLYMORPHISMS IN LINKAGE DISEQUILIBRIUM THAT FORM AN AMD-ASSOCIATED HAPLOTYPE BLOCK. Chr 10 position r2 LDlink/ D' LDlink/ SNP (GPCh37) REF/ALT Allele HaploReg HaploReg AMD References rs61871744 124,203,787 T/C 0.96/0.94 0.99/0.99 rs59616332 124,208,562 ATAAAC/- 0.96/NA 0.99/NA rs11200630 124,209,684 T/C 0.99/0.98 1/0.99 rs61871745 124,210,369 G/A 0.99/0.98 1/0.99 rs11200632 124,211,536 A/G 0.99/0.99 1/1 rs11200633 124,211,596 C/T 0.99/0.98 1/1 rs61871746 124,212,913 T/C 1/1 1/1 rs61871747 124,213,046 C/T 1/1 1/1 rs370974631 124,213,143 AA/- 0.93/NA 1/NA rs200227426 124,213,671 C/A 0.96/NA 0.99/NA rs201396317 124,213,674 C/A 0.96/NA 0.99/NA rs199637836 124,213,677 C/A 0.96/NA 0.99/NA rs11200634 124,213,680 C/A 0.96/NA 0.99/NA rs75431719 124,213,688 C/A 0.96/NA 0.99/NA 22, 23, 24, 25, 26, 27, 28, 36, rs10490924 124,214,448 G/T Reference SNP Reference SNP and additional 140 refs rs144224550 124,214,600 - /GT 1/NA 1/NA rs36212731 124,214,976 G/T 0.99/1 1/1 rs36212732 124,215,198 A/G 1/1 1/1 rs36212733 124,215,211 T/C 1/1 1/1 rs3750848 124,215,315 T/G 1/1 1/1 29 rs3750847 124,215,421 C/T 1/1 1/1 30 rs3750846 124,215,565 T/C 1/1 1/1 1, 29 rs566108895 124,216,823 G/T 0.91/NA 0.99/NA rs3793917 124,219,275 C/G 0.99/0.98 1/0.99 29, 31, 32, 33 rs3763764 124,220,061 A/G 0.98/0.98 0.99/0.99 17, 18, 19, 20, 21, 22, 23, and rs11200638 124,220,544 G/A 0.98/0.9 0.99/0.97 additional 100 refs rs1049331 124,221,270 C/T 0.97/0.96 0.99/0.99 34, 37 rs2293870 124,221,276 G/C,T NA/0.9 NA/0.95 34, 38, 39 rs2284665 124,226,630 G/T 0.96/0.94 0.99/0.98 35 rs60401382 124,227,624 C/T 0.84/0.82 0.98/0.97 rs11200643 124,229,203 C/T 0.82/0.8 0.96/0.94 rs58077526 124,230,024 A/C 0.91/0.89 0.96/0.95 rs932275 124,231,464 G/A 0.93/0.89 0.97/0.96 29 rs2142308 124,234,037 G/C 0.92/0.89 0.97/0.96 The SNP rs10490924 is the reference SNP used to obtain r2 and D’ values in both the HaploReg and LDlink websites. In the 1000 Genome project European population there are 34 polymorphisms, including rs10490924, in linkage disequilibrium using the inclusion criterion r2 ≥0.8 [11,12]. LDlink r2 refers to the strength of the association of the alleles at the queried SNP with rs10490924. LDlink D’ measures linkage disequilibrium normalized for allele frequency. NA = Not Available. 319 Molecular Vision 2017; 23:318-333 <http://www.molvis.org/molvis/v23/318> © 2017 Molecular Vision Figure 1. Diagram of the chromosome 10q26 region containing the PLEKHA1, ARMS2, and HTRA1 genes, as well as the locations of the SNPs that have been associated with risk for AMD by published GWASs and genetic studies. 59338, OMIM: 607772), age-related maculopathy-2 (ARMS2; 6. The mRNA levels are expressed as rank normalized gene gene ID: 387715, OMIM: 611313), and high temperature expression [15]. The effect size of an eQTL is the change in requirement protein A1 (HTRA1; gene ID: 5654, OMIM: the value of the standardized gene expression level with each 602194). It is even conceivable that a more distant gene actu- extra copy of the alternative (ALT) allele relative to the refer- ally confers the risk for AMD. ence allele, conditional to all other adjustments (gender, prob- We searched for associations between AMD-risk SNPs abilistic estimation of expression residuals factors, genotype in the 10q26 region and the expression of closely linked principal components, and genotyping platforms).
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  • 1 Fibrillar Αβ Triggers Microglial Proteome Alterations and Dysfunction in Alzheimer Mouse 1 Models 2 3 4 Laura Sebastian

    1 Fibrillar Αβ Triggers Microglial Proteome Alterations and Dysfunction in Alzheimer Mouse 1 Models 2 3 4 Laura Sebastian

    bioRxiv preprint doi: https://doi.org/10.1101/861146; this version posted December 2, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Fibrillar triggers microglial proteome alterations and dysfunction in Alzheimer mouse 2 models 3 4 5 Laura Sebastian Monasor1,10*, Stephan A. Müller1*, Alessio Colombo1, Jasmin König1,2, Stefan 6 Roth3, Arthur Liesz3,4, Anna Berghofer5, Takashi Saito6,7, Takaomi C. Saido6, Jochen Herms1,4,8, 7 Michael Willem9, Christian Haass1,4,9, Stefan F. Lichtenthaler 1,4,5# & Sabina Tahirovic1# 8 9 1 German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany 10 2 Faculty of Chemistry, Technical University of Munich, Garching, Germany 11 3 Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians Universität München, 12 81377 Munich, Germany 13 4 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany 14 5 Neuroproteomics, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, 15 Munich, Germany 16 6 Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science Institute, Wako, 17 Saitama 351-0198, Japan 18 7 Department of Neurocognitive Science, Nagoya City University Graduate School of Medical 19 Science, Nagoya, Aichi 467-8601, Japan 20 8 Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität München, 81377 21 Munich, Germany 22 9 Biomedical Center (BMC), Ludwig-Maximilians Universität München, 81377 Munich, Germany 23 10 Graduate School of Systemic Neuroscience, Ludwig-Maximilians-University Munich, Munich, 24 Germany. 25 *Contributed equally 26 #Correspondence: [email protected] and [email protected] 27 28 Running title: 29 Microglial proteomic signatures of AD 30 Keywords: Alzheimer’s disease / microglia / proteomic signatures / neuroinflammation / 31 phagocytosis 32 1 bioRxiv preprint doi: https://doi.org/10.1101/861146; this version posted December 2, 2019.